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Toxicological Sciences 66, 336-346 (2002)
Copyright © 2002 by the Society of Toxicology

SAFETY EVALUATION

Prediction of Skin Irritation from Organic Chemicals Using Membrane-Interaction QSAR Analysis

Kiran Kodithala*, A. J. Hopfinger*,1, Edward D. Thompson{dagger} and Michael K. Robinson{dagger}

* Laboratory of Molecular Modeling and Design, M/C-781, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612–7231; and {dagger} The Procter & Gamble Company, Miami Valley Research Laboratories, P.O. Box 538707, Cincinnati, Ohio 45253–8707

Membrane-interaction (MI) quantitative structure activity relationship (QSAR) analysis was carried out for a training set of 22 hydroxy organic compounds for which the Draize skin irritation scores, PII, had been determined. Significant MI-QSAR models were constructed in which skin irritation potency is predicted to increase with (1) increasing effective concentration of the compound available for uptake into phospholipid-rich regions of a cellular membrane, (2) increasing binding of the compound to the phospholipid-rich regions of a cellular membrane, and (3) the chemical reactivity of the compound as reflected by the highest occupied molecular orbital (HOMO) and/or lowest unoccupied molecular orbital (LUMO) of the molecule. Overall, the MI-QSAR models constructed for skin irritation are very similar, with respect to the types of descriptors, to those found for eye irritation. In turn, the skin irritation MI-QSAR models suggest a similar molecular mechanism of action to that postulated for eye irritation from MI-QSAR analysis. Significant and predictive QSAR models cannot be constructed unless test compound-membrane interaction descriptors are computed and used to build the QSAR models.

Key Words: QSAR; membrane interaction; skin irritation.


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